"Home" genetic testing: the opinion of an interested specialist

Genetic testing and paternalism in medicine

Ekaterina Pomerantseva, "Biomolecule"

The Internet is actively discussing the situation with the American company 23andMe – the FDA orders it to stop directly selling genetic testing kits to customers due to the lack of a medical license. A large Russian article on this topic was published, ending as follows: "The dispute between 23andMe and the FDA, in fact, boils down to the question of whether it is worth giving people free access to their genetic data or they are so dangerous that it is better to leave this right only to specialists. It is difficult to say how this not so much a legal, as a worldview dispute will end" [1].

I agree that the dispute is ideological, and it is good that the discussion on this topic arose explicitly, and not behind the scenes in the bowels of ministries and departments. Now all parties have the opportunity to be heard, and the general public can form their attitude to genetics not on the basis of feature films that are far from reality, but by analyzing professional opinions expressed in the public press.

I will try to describe several basic approaches and emphasize both their strengths and vulnerabilities. It seems to me that you can try to evaluate them objectively, even if you yourself have a certain, formed position.

Let's start with a description of the problem. To do this, first of all, it is necessary to imagine what technological capabilities we have for obtaining and analyzing genetic data today, taking into account the price and, consequently, availability. So that

Part 1. What information geneticists can tell a person right now, and what information they can'tA few decades ago, scientists learned to check a person for the presence of certain (described in the scientific literature) mutations that lead to hereditary diseases, such as hemophilia.

Traditionally, various variants of PCR (polymerase chain reaction) technology are used for this, which allows to "multiply" the DNA fragment of interest in a test tube and, having received a sufficient amount of biological material, to conduct molecular biological studies (fragment analysis, sequencing, etc.) In the last decade, the technology of DNA microchips designed for simultaneous verification is gaining popularity the presence of a large number of previously described mutations, the position of which in the genome is well known (Fig. 1). For more information about the methods of molecular biology, see the article "The most important methods of molecular biology and genetic engineering" [2].

Figure 1. Comparison of the leading methods of molecular genetic diagnostics.
All these methods are aimed at finding out the information contained in human DNA.
More details about them are described in the article [2].

The results of such an analysis can be fairly confidently interpreted in terms of medical genetics. The relationship of the studied mutations with diseases is known and the probability with which this or that combination of mutations will lead to disease. To help those people who have dangerous mutations, methods of prenatal diagnosis and preimplantation genetic diagnosis (PGD) have been developed. In some cases, a specific treatment has been created.

The latest methods of genetic analysis based on genome-wide sequencing expand the diagnostic field from a set of individual mutations (albeit large) to the entire DNA sequence: here you can already find mutations not previously described in the literature and "invisible" to the microchip method due to the lack of their exact "coordinates". However, there are great difficulties with the interpretation of such "new" mutations. They are partly related to the complexity of the bioinformatic task of processing huge amounts of data without losing significant information. But the biggest obstacle is that, without having information about the health of people with the same mutation, it is impossible to make confident predictions about a particular patient.

Figure 2. DNA microchip technology. The patient's DNA is hybridized with a short fragment of "reference" DNA fixed on the surface of the DNA microchip. After hybridization, the reference chain is lengthened by one nucleotide at the very place where the desired mutation is located. The nucleotides involved in the completion of DNA are labeled with various fluorescent labels, and by registering fluorescence in a laser beam, it is possible to determine which nucleotide was included in the DNA and, consequently, which mutation the patient's DNA contains.In addition to mutations, among the genetic variations, polymorphism is also distinguished – the presence of several gene variants in the population.

In medical genetics, it is customary to distinguish mutations as clinically significant variants, and to call polymorphisms such variants in which the clinical significance is weak or incomprehensible. Polymorphisms in different genes are very common and to some extent explain why, for example, people react differently to medications or digest food (digest milk, for example). There are such polymorphisms, the analysis of which provides information rather than for treatment, but for interest – why taste sensitivity differs, how genes affect character or even athletic inclinations. The study of alleles in special genetic loci is also practiced (an allele is a broader concept than polymorphism, meaning any variants of the same gene), which makes it possible to determine the origin of a person on the paternal and maternal lines.

And you can also test for predisposition to multifactorial diseases – such as cancer, diabetes, coronary heart disease. In each case, many genes involved are known, in most of which both significant mutations and polymorphisms with unclear meaning have been identified. However, in addition to this, non-genetic factors have a huge impact on the risk of developing such diseases, so it is simply impossible to make an unambiguous forecast based on genetic tests.

In general, it should be clearly understood: the further away from medicine (with its long and carefully collected clinical data), and the more genes involved in the regulation of the process, the more difficult it is to tell the patient something definite based on the results of genetic testing. And then, when we hand a person a sheet with the results, he looks at it in bewilderment, and then looks up and says: "So what?" Unfortunately, there is often nothing to answer this question.

Part 2. What genetic services are offered to clientsTraditionally, geneticists refer patients with suspected hereditary disease for molecular genetic confirmation.

Such an analysis can be called, for example, "search for frequent mutations in the NNN gene". Then the referring doctors explain to the patients the meaning of the results obtained in the laboratory.

It is less common, but it is already quite possible to sequence the complete nucleotide sequence of the gene "suspected" as the cause of the disease. This is also a well-established, proven method [3, 4]. It is used when frequent mutations are unknown in the gene (i.e. they can equally likely happen in different places) or nothing was found among the frequent ones. Then it will be more effective for analysis to know the complete sequence of the gene, and not just variations on individual nucleotides.

Figure 3. The principle of genotyping using APEX technology. After the reaction, the glow of the points on the microchip corresponding to the mutations is recorded in four wave ranges. This is how the sequence is determined at the mutation point or SNP. Both semantic and antisense sequences are hybridized [5].There are also microchips (and soon they will appear on the market and based on NGS, "new generation sequencing")

screening panels designed for healthy people who want to check which mutations they are carriers of, what risks this carries for themselves and their children (Fig. 2, 3). Such microchips are focused on identifying a large number of mutations in different genes. Since the prevalence of mutations among different peoples can vary greatly (see the table), chips designed with population data for a specific group of people have a great advantage – a panel for Ashkenazi Jews, a panel for Mediterranean residents, etc. There is also a Russian chip "Ethnogen", designed for residents of Russia and its neighbors.

There are polymorphism panels – commercial kits for testing for all kinds of "predispositions to". Doctors sometimes also send doctors for such an examination, although more often they are no longer geneticists, since the reputation of such tests is much more dubious. Their results are not often of clinical significance. This may be due both to the fact that the disease is multifactorial, and to the fact that clinicians do not have the opportunity (or desire, or experience) to change treatment depending on genetic data. Some firms advertise such tests among the general population, and people decide to conduct such a survey themselves, and then search the Internet for a long time for someone to take up the interpretation of the results obtained.

There are also frankly non–clinical sets for genetic examination - such as the study of genogeography, i.e. the origin of a person, his proximity to certain peoples from different parts of the planet. And there are also combined panels, which include both mutations that lead to diseases, and incomprehensible polymorphisms, and tests that are clearly unintended for medical interpretation.

Part 3. What is the conflict?The company 23andMe mentioned at the very beginning of the article provides just a "combined type" testing service based on microchip technology.

Their panel included "strong" (significant) and "weak" mutations, polymorphisms, allelic variants, data on origin – everything that could be done within the framework of the microchip analysis format. This is their first feature – the versatility of the test. The second is accessibility! Now their service costs only $ 99. From the point of view of screening coverage, this is, of course, a huge plus. And the third feature is the lack of "live" genetic counseling. It is replaced by an automated online expert system, in which there is a function to "consent to the provision of information" in relation to certain mutations.

Thus, 23andMe has combined both "entertainment" and clinically oriented medical genetics in one service.

Than angered everyone at once.

Because there are several positions, from different sides hostile to the concept of 23andMe.

On the one hand, supporters of the use of genetic tests "with benefit" really dislike entertaining genetics when it is disguised as a medical service. In fact, it really harms the reputation of genetics as such. For example, tortured doctors often react nervously to the words of the patient "And here we also did the test ourselves, what does it mean?" Because the answer – "Yes, it doesn't mean anything, it's fortune–telling, which does not give clinically reliable information!" - does not suit the patient categorically: "How so, it's the same the advanced method, we gave away so much money! Doctor, you just don't understand!" Further, even in the case of a personal consultation, the patient's disappointment is no less – he thought that he would now be told how to live on, but it turns out that all the recommendations boil down to "well, you can't smoke, and alcohol should be limited." (The differences between medical and "entertainment" genetics are highlighted in Figure 4.)

The most annoying thing is that then it is very difficult for both these patients and these doctors to explain that there are real medical genetics, and mutations important for the treatment and prognosis of the disease. It would be better if they were engaged in them, and not entertaining fortune-telling on polymorphisms. An illustration of this problem may be an old medical joke: "Before you prescribe an analysis, think about what you will do if it is A) negative and B) positive. If the answers are the same, there is no need for analysis."

Figure 4. The fundamental difference between medical (on a green background) and entertainment genetics
it consists in the need for active action after passing the test and getting an alarming result.

On the other hand, other adherents of the same medical genetics believe that serious research should be carried out exclusively on the prescription of a doctor. And the results should not just be reported to the patient, but they should be consulted with an explanation of the risks. And that doctors, and not geneticists-researchers, should certainly do it. So clinically significant diagnostics should be left to medical laboratories with special certificates, but directly to customers you can sell just such a commercial service as entertainment genetics.

Part 4. What are they all afraid of and what arguments are there to justify the 23andMe strategy?Each such position has its own reasons.

For simplicity, I propose to consider an ideal situation where there are only ideological, or, as it was suggested above, ideological contradictions. There is neither the interests of Big Pharma, nor the lobby of insurance companies, nor the interest of large corporations. And there is only a sincere desire to benefit the patient. Only everyone imagines it differently.

Conditional "doctors" quite rightly believe that genetic information can bring not only benefits, but also harm. Firstly, a person who has been informed about the mutation may simply panic. There are known cases of suicide when receiving test results for particularly severe incurable diseases (such as Huntington's chorea, for example). Secondly, a person may misunderstand the significance of risks and their ability to manage them. He may not understand, for example, that one copy of a mutation is sometimes harmless at all – only two cause the disease. But sometimes one is enough – and then, on the contrary, there is a chance that the patient will underestimate the threat. There is also a risk of family breakdown – when a person who finds out that they and their spouse are carriers of the same mutation, instead of prenatal diagnosis to prevent the disease in the offspring, decides to leave the spouse.

Figure 5. The company "guarantees!"

Conditional "researchers" believe that information is a force, there cannot be much of it, and it should be accessible (although they are also insured, see Figure 5). And this approach also has its own arguments. A positive argument is that the search for information has now become much easier due to the appearance of online resources. And a motivated person, wanting to understand what his results mean, may well find information on the Internet, seek online advice or, finally, come to an appointment with a geneticist on his own - not because this is an obligatory stage of a genetic examination, but because he found something about which he needs to know more.

And the negative argument is the sad understanding that the ideal situation "for each patient to have a personal geneticist, and let no one leave unperceived" is still completely unattainable. There are very few geneticists, and the cost of their services is high. And, alas, there is no guarantee that a geneticist will give out more qualified information than can be found on the Internet in five minutes. Because genetics develops very quickly, information is updated rapidly on the web, but doctors do not always have time to track them. After all, they do not always speak English, visit the right places on the web, or even just know about the existence of the OMIM database (a catalog of known hereditary diseases). So it turns out that in such realities, a patient who reads in foreign languages and looks at least into the English-language wikipedia (although it is not uncommon now for patients who already use both OMIM and PubMed) is already in a more advantageous position than a doctor who does not read English, who is used to relying on textbooks, according to which he was once taught, and translated literature, which often becomes obsolete before it is published here.

In defense of 23andMe specifically, I would like to note that, although they do not provide "live" consultations, they do have an excellent system for issuing personalized information through a special website. It describes in detail, competently and in understandable language what this or that "find" means. Of course, the system does not track feedback, cannot assess whether the client has understood the explanations, whether he needs additional support. But there, if possible, the "potentially dangerous" issues are explained very carefully, the recommendation to consult a doctor in real life is repeated many times, the dosed information is provided so that a person, before seeing any part of the results, thinks whether he is ready for this.

Part 5. The principle of "do no harm" and paternalism in medicine – where is the border?Doctors are taught that the first task of a doctor is not to cause additional harm to the patient by his actions.

Because of this, they often form an arrogant attitude towards the patient as an unreasonable child. This attitude is called paternalism.

Paternalists, in their desire to protect the patient from iatrogenic (inflicted by doctors) trauma, shift responsibility for a person's health from himself to his doctor.

Especially inappropriate then, by the way, are the claims that patients do not follow the prescriptions and generally behave irresponsibly and infantile. Well, of course – responsibility was taken away from them, so they accepted the role of children.

And if you treat patients as reasonable adults, then the responsibility is shared. The doctor is responsible for providing competent advice when he is approached for this consultation. To help put it in simple language and disseminate information in the area where he is competent. And the patient is responsible for his decision to take the test, and seek advice or seek information himself. And then, having come to the doctor, he obviously trusts him more than when he is dragged to a consultation by force.

And now attention, a question. Isn't this patient too "ideal"? Does he meet in reality? Or is it the same unattainable abstraction as an accessible-qualified-respectful geneticist?

And it is precisely this question that is ideological. It's a matter of faith in people.

Conclusion. Personal position, or the ideal world as I see itI am a medical doctor by education, a researcher by second education, and I work in the field of genetic testing and counseling (I head the laboratory "Genetiko" and PGD consulting at the Institute of Human Stem Cells).

I studied genetics both in Russia and in the USA, and, of course, compared different approaches. And I have my own opinion about "how to do it right", and I have seriously revised it over the years and most likely I will continue to correct it with the accumulation of experience.

It seems to me that genetic services should be available. I don't like "entertainment genetics", considering that it has caused a lot of damage to the reputation of the business we are engaged in. But the same 23andMe, I would forgive all these flirtations with polymorphisms just because their test costs only $ 99. And thanks to such an affordable price, thousands of people were able to find out in time not only about their origin and the ability to smell different smells, but also about the fact that they have a significant mutation, because of which a sick child may be born. And they went to the doctor, and they were told about PGD (preimplantation genetic diagnosis – testing of embryos during IVF [6, 7]) and conducted it, and instead of a sick child they had a healthy one. And, yes, of course, it would be better for such a test to be prescribed and explained by doctors at a personal consultation. But if, because of this, the price becomes not $ 99, but $ 999, then there will be much fewer such people, since few people will spend such an amount "just like that". Instead of mass screening, it will be a service "for the rich". And everyone else will continue to have sick children.

[…]

So in real modern conditions, this approach seems to me to be the most correct. There is a service called "genetic testing". This should be a carefully prepared and tested screening panel with mutations that are common and clinically significant in a particular population. And this service should be widely available and "integrated" into the healthcare system, providing a truly massive screening of the population.

For people undergoing such an examination, a convenient and understandable system of automatic counseling should be created, in which, in addition to background information, cases when a patient needs to consult a doctor for personal advice would be specially highlighted. And also that the important mutations found should be carefully checked by an independent method. And in this system, links to databases and clinical studies and other reliable sources should be contextually placed, where the patient, if desired, will be able to delve independently, without fear of running into the "wave genome" and other pseudoscience in his search on the Internet. In addition, it is very important that there are links to support groups and patient organizations that do not allow a person to be left alone with a serious problem. In Russia, such groups are already appearing too – in the format of both thematic blogs and websites, as well as large organizations holding annual conferences on rare diseases.

To work with such patients, special psychologists will also be needed, and those who know genetics – so that they do not try to explain hereditary diseases with bad karma or the fact that mom did not like.

And we need a system of training geneticists and genetic consultants, and completely different from what it is now. This is a separate complex issue, and here, by the way, there is something to learn from the Americans.

Already, there is almost everything to create such an integrated approach. Methods to reduce the cost of analysis, information for creating an online consulting system, a few but qualified geneticists to work with complex cases, experts who are ready to train new doctors, patients who are ready to delve into the essence of their problem and support other people with a similar situation. This is all necessary first of all – to organize.

And we will definitely do it.

LiteratureLenta.ru : "Spitting into the future";

2. biomolecule: "The most important methods of molecular biology and genetic engineering";
3. biomolecule: "454-sequencing (high-performance DNA pyrosequencing)";
4. biomolecule: "The code of life: to read does not mean to understand";
5. Tonisson et al., Arrayed Primer Extension Microarrays for Molecular Diagnostics. Oxford: Academic Press, 2010, 267–284;
6. Brezina P.R. (2013). Preimplantation Genetic Testing in the 21st Century: Uncharted Territory. Clin. Med. Insights Reprod. Health 7, 17–21;
7. Biomolecule: ""For in vitro fertilization" is not a toast, but a Nobel Prize!".

Portal "Eternal youth" http://vechnayamolodost.ru19.03.2014